Aryl-aryl bond formation has elicited much interest in modern organic synthesis. This axially chiral bond is often found in natural products such as alkaloids (Bringmann et al., 1995; Furukawa et al., 1983; Bringmann et al., 2001), such as vancomycin, and is prevalent in biologically active parts of pharmaceuticals (Gallant et al., 2002; Sasaki et al., 2003, Hotzel et al., 2002) and agrochemical specialties (Ikegaya et al., 1999; Hatanaka et al., 1996), as well as in materials science (Bringmann et al., 1997; Lee et al., 2002; Messner et al., 2000). Development of a synthetic method for designing similarly structured compounds has been aided by advances in transition metal catalysis, namely, palladium-catalyzed cross-coupling reaction (Larock et al., 1995).
The present inventor has developed a unique orthogonal solid phase synthetic pathway for preparing a highly pure trisubstituted triazine library, in which three types of building blocks were assembled by chemically orthogonal reactions (Moon et al., 2002; Bork et al., 2003; Chang et al., U.S. Ser. No. 10/267,043, filed Oct. 9, 2002, the entire contents of which are hereby incorporated by reference). A series of compounds from the library, tubulyzines, demonstrated a significant biological activity by inhibiting tubulin polymerization (Moon et al., 2002). However, in this approach, bond formation was restricted to amine or several alcohol functionalities around the triazine scaffold.
The vinca alkaloids, including vinblastine and vincristine, have been used for treating cancers such as leukemias and lymphomas for a long time, and taxol derivatives have recently been used for treating breast cancers. However, these drugs are inherently toxic, especially neurotoxic, and the compounds are low in solubility and are not readily available in quantity. As most of the lead compounds originated from naturally occurring sources (plants, sponges, mollusks, bacteria), chemical modification might be a straightforward approach for improving the activity and properties of the drugs while reducing side effects. Serious efforts have been made to synthesize derivatives of vinca alkaloids, colchicines, taxol, and related compounds, but modification of the complicated natural products without adversely affecting utility has so far been difficult.
Solution-phase Suzuki couplings of heterocyclic aryl halides, such as halopyrimidines (Schomaker et al., 2001; Cooke et al., 2001), halopyridines (Zhang et al., 1998), halopurines (Ding et al., 2001; Havelkova et al., 2001), and halotriazines (Cooke et al., 2001; Janietz et al., 2002) have been studied in the literature. The Suzuki coupling has been further extended to solid phase (Hassan et al., 2002) both in halopyrimidines (Wade et al., 2003; Ding et al., 2002) and halopurines (Ding et al., 2002; Brun et al., 2002) yet has not been developed for the triazine scaffold.